Evaluation of Immunocompetence and Biomarkers of Tolerance in Chimeric and Immunosuppression-free Kidney Allograft Recipients

Joseph R. Leventhal; John Galvin; Michael G. Ison; Chris Yuhsuen Feng; Ruchuang Ding; John R. Lee; Carol Li; James M. Mathew; Lorenzo Gallon; Meg Gibson; Dianne Belshe; David J. Tollerud; Eric Gornstein; Manikkam Suthanthiran; Suzanne T. Ildstad

doi:10.1097/TP.0000000000004666

Evaluation of Immunocompetence and Biomarkers of Tolerance in Chimeric and Immunosuppression-free Kidney Allograft Recipients

Joseph R. Leventhal, John Galvin, Michael G. Ison, Chris Yuhsuen Feng, Ruchuang Ding, John R. Lee, Carol Li, James M. Mathew, Lorenzo Gallon, Meg Gibson, Dianne Belshe, David J. Tollerud, Eric Gornstein, Manikkam Suthanthiran, Suzanne T. Ildstad^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Background. Thirty-seven patients have received a living-donor kidney transplant in a phase 2 study designed to induce tolerance with facilitated allogeneic hematopoietic stem cell transplant. The study protocol is based on tolerogenic CD8⁺/T-cell receptor^-facilitating cells (FCR001; also including hematopoietic stem cells and αβ-T-cell receptor⁺T cells) and low-dose, nonmyeloablative conditioning. Persistent chimerism allowing full immunosuppression (IS) withdrawal was achieved in 26 patients (time off IS 36-123 mo). Methods. We evaluated biomarkers of tolerance through urinary cell mRNA profiling and immunocompetence to respond to vaccination in these patients. We also assessed kidney function and metabolic parameters compared with standard-of-care patients on IS. Results. Persistently chimeric patients retained chimerism after removal of IS and remained rejection free without donor HLA-specific antibody development. The presence of donor chimerism at >50% correlated with a signature of tolerance in urinary cell mRNA profiles, with a uniquely elevated increase in the ratio of cytotoxic T lymphocyte-associated protein 4 to granzyme B mRNA. Tolerance was associated with protection from recurrence of immune-mediated causes of kidney disease. Tolerant participants were safely vaccinated, developed protective immune responses, and did not lose chimerism after vaccination. When compared with kidney transplant recipients treated with standard IS, tolerant participants showed stable kidney function and reduced medication use for hypertension and hyperlipidemia. Conclusions. These results suggest that elimination of IS has distinct advantages in living-donor kidney allograft recipients.

Original language	English (US)
Pages (from-to)	E257-E268
Journal	Transplantation
Volume	107
Issue number	10
DOIs	https://doi.org/10.1097/TP.0000000000004666
State	Published - Oct 1 2023

Funding

E.G., D.J.T., and S.T.I. have an equity interest in Talaris Therapeutics, Inc., a cell therapy biotechnology company. M.G.I. received research support, paid to Northwestern University Feinberg School of Medicine, from GlaxoSmithKline; royalties from UpToDate; and was a paid consultant for Adagio, ADMA Biologics, Adamis, AlloVir, Atea, Cidara, Genentech, Janssen, Roche, Shionogi, Takeda, Talaris Therapeutics, Inc., and Viracor Eurofins; all of these activities ceased December 4, 2022. J.L. received research support via an investigator-initiated research grant from BioFire Diagnostics, LLC; receives royalties from patent US-2020-0048713-A1, entitled “Methods of Detecting Cell-Free DNA in Biological Samples,” licensed to Eurofins Viracor; and receives speaker fees from Astellas. M.S. has a Consultancy Agreement and a Research Collaborative Agreement with CareDx, Inc., Brisbane, CA.

ASJC Scopus subject areas

Transplantation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Leventhal, J. R., Galvin, J., Ison, M. G., Feng, C. Y., Ding, R., Lee, J. R., Li, C., Mathew, J. M., Gallon, L., Gibson, M., Belshe, D., Tollerud, D. J., Gornstein, E., Suthanthiran, M., & Ildstad, S. T. (2023). Evaluation of Immunocompetence and Biomarkers of Tolerance in Chimeric and Immunosuppression-free Kidney Allograft Recipients. Transplantation, 107(10), E257-E268. https://doi.org/10.1097/TP.0000000000004666

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title = "Evaluation of Immunocompetence and Biomarkers of Tolerance in Chimeric and Immunosuppression-free Kidney Allograft Recipients",

abstract = "Background. Thirty-seven patients have received a living-donor kidney transplant in a phase 2 study designed to induce tolerance with facilitated allogeneic hematopoietic stem cell transplant. The study protocol is based on tolerogenic CD8+/T-cell receptor-facilitating cells (FCR001; also including hematopoietic stem cells and αβ-T-cell receptor+T cells) and low-dose, nonmyeloablative conditioning. Persistent chimerism allowing full immunosuppression (IS) withdrawal was achieved in 26 patients (time off IS 36-123 mo). Methods. We evaluated biomarkers of tolerance through urinary cell mRNA profiling and immunocompetence to respond to vaccination in these patients. We also assessed kidney function and metabolic parameters compared with standard-of-care patients on IS. Results. Persistently chimeric patients retained chimerism after removal of IS and remained rejection free without donor HLA-specific antibody development. The presence of donor chimerism at >50% correlated with a signature of tolerance in urinary cell mRNA profiles, with a uniquely elevated increase in the ratio of cytotoxic T lymphocyte-associated protein 4 to granzyme B mRNA. Tolerance was associated with protection from recurrence of immune-mediated causes of kidney disease. Tolerant participants were safely vaccinated, developed protective immune responses, and did not lose chimerism after vaccination. When compared with kidney transplant recipients treated with standard IS, tolerant participants showed stable kidney function and reduced medication use for hypertension and hyperlipidemia. Conclusions. These results suggest that elimination of IS has distinct advantages in living-donor kidney allograft recipients.",

author = "Leventhal, {Joseph R.} and John Galvin and Ison, {Michael G.} and Feng, {Chris Yuhsuen} and Ruchuang Ding and Lee, {John R.} and Carol Li and Mathew, {James M.} and Lorenzo Gallon and Meg Gibson and Dianne Belshe and Tollerud, {David J.} and Eric Gornstein and Manikkam Suthanthiran and Ildstad, {Suzanne T.}",

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Leventhal, JR, Galvin, J, Ison, MG, Feng, CY, Ding, R, Lee, JR, Li, C, Mathew, JM, Gallon, L, Gibson, M, Belshe, D, Tollerud, DJ, Gornstein, E, Suthanthiran, M & Ildstad, ST 2023, 'Evaluation of Immunocompetence and Biomarkers of Tolerance in Chimeric and Immunosuppression-free Kidney Allograft Recipients', Transplantation, vol. 107, no. 10, pp. E257-E268. https://doi.org/10.1097/TP.0000000000004666

TY - JOUR

T1 - Evaluation of Immunocompetence and Biomarkers of Tolerance in Chimeric and Immunosuppression-free Kidney Allograft Recipients

AU - Leventhal, Joseph R.

AU - Galvin, John

AU - Ison, Michael G.

AU - Feng, Chris Yuhsuen

AU - Ding, Ruchuang

AU - Lee, John R.

AU - Li, Carol

AU - Mathew, James M.

AU - Gallon, Lorenzo

AU - Gibson, Meg

AU - Belshe, Dianne

AU - Tollerud, David J.

AU - Gornstein, Eric

AU - Suthanthiran, Manikkam

AU - Ildstad, Suzanne T.

PY - 2023/10/1

Y1 - 2023/10/1

N2 - Background. Thirty-seven patients have received a living-donor kidney transplant in a phase 2 study designed to induce tolerance with facilitated allogeneic hematopoietic stem cell transplant. The study protocol is based on tolerogenic CD8+/T-cell receptor-facilitating cells (FCR001; also including hematopoietic stem cells and αβ-T-cell receptor+T cells) and low-dose, nonmyeloablative conditioning. Persistent chimerism allowing full immunosuppression (IS) withdrawal was achieved in 26 patients (time off IS 36-123 mo). Methods. We evaluated biomarkers of tolerance through urinary cell mRNA profiling and immunocompetence to respond to vaccination in these patients. We also assessed kidney function and metabolic parameters compared with standard-of-care patients on IS. Results. Persistently chimeric patients retained chimerism after removal of IS and remained rejection free without donor HLA-specific antibody development. The presence of donor chimerism at >50% correlated with a signature of tolerance in urinary cell mRNA profiles, with a uniquely elevated increase in the ratio of cytotoxic T lymphocyte-associated protein 4 to granzyme B mRNA. Tolerance was associated with protection from recurrence of immune-mediated causes of kidney disease. Tolerant participants were safely vaccinated, developed protective immune responses, and did not lose chimerism after vaccination. When compared with kidney transplant recipients treated with standard IS, tolerant participants showed stable kidney function and reduced medication use for hypertension and hyperlipidemia. Conclusions. These results suggest that elimination of IS has distinct advantages in living-donor kidney allograft recipients.

AB - Background. Thirty-seven patients have received a living-donor kidney transplant in a phase 2 study designed to induce tolerance with facilitated allogeneic hematopoietic stem cell transplant. The study protocol is based on tolerogenic CD8+/T-cell receptor-facilitating cells (FCR001; also including hematopoietic stem cells and αβ-T-cell receptor+T cells) and low-dose, nonmyeloablative conditioning. Persistent chimerism allowing full immunosuppression (IS) withdrawal was achieved in 26 patients (time off IS 36-123 mo). Methods. We evaluated biomarkers of tolerance through urinary cell mRNA profiling and immunocompetence to respond to vaccination in these patients. We also assessed kidney function and metabolic parameters compared with standard-of-care patients on IS. Results. Persistently chimeric patients retained chimerism after removal of IS and remained rejection free without donor HLA-specific antibody development. The presence of donor chimerism at >50% correlated with a signature of tolerance in urinary cell mRNA profiles, with a uniquely elevated increase in the ratio of cytotoxic T lymphocyte-associated protein 4 to granzyme B mRNA. Tolerance was associated with protection from recurrence of immune-mediated causes of kidney disease. Tolerant participants were safely vaccinated, developed protective immune responses, and did not lose chimerism after vaccination. When compared with kidney transplant recipients treated with standard IS, tolerant participants showed stable kidney function and reduced medication use for hypertension and hyperlipidemia. Conclusions. These results suggest that elimination of IS has distinct advantages in living-donor kidney allograft recipients.

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Evaluation of Immunocompetence and Biomarkers of Tolerance in Chimeric and Immunosuppression-free Kidney Allograft Recipients

Abstract

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UN SDGs

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